T cells play a central role in immunity to viruses but our knowledge of what is required at the cellular and molecular level to generate an anti-viral T cell response is not as extensive as it needs to be in order to formulate effective and long-lasting vaccines based on virus vectors. We propose to study the requirement and role of several TNF/TNFR superfamily molecules in the development of the anti-viral T cell response to vaccinia virus. We propose that these molecules might be targets for improving our ability to effectively vaccinate. Poxvirus-based vectors are being used as vaccine candidates for many pathogens that we have failed to effectively control, including HIV, HSV, malaria, and tuberculosis. We have found that two interactions within the TNFR family, namely OX40/OX40L and CD27/CD70, play essential non-redundant roles in directing the priming of CD8 and CD4 T cells induced by the most virulent strain of one poxvirus, vaccinia virus. Our future studies propose to understand how targeting these molecules, and new members of the TNFR family, can promote quantitative and qualitative aspects of T cell memory that will allow attenuated poxvirus vectors to be used successfully for vaccination while maintaining the safety of these vaccines. By understanding how the availability of the TNFR proteins and their TNF ligands are controlled by the immune system and the virus, we hope to gain greater insight into how virus-reactive T cells are regulated, which will be of use for understanding how protection against many viruses can be achieved. By focusing on molecules such as those in the TNFR/TNF superfamilies, this is likely to lead to development of new clinical targets for promoting more efficient vaccination strategies.